Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Sendai.
Department of Physical Therapy, Faculty of Health Science, Juntendo University, Tokyo.
J Hypertens. 2022 Feb 1;40(2):327-337. doi: 10.1097/HJH.0000000000003012.
Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats.
Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks.
Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks.
Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.
几项临床研究报告称，黄嘌呤氧化还原酶抑制剂具有降压和肾脏保护作用，但它们的机制尚未完全确定。本研究旨在通过研究新型选择性黄嘌呤氧化还原酶抑制剂非布司他在 Dahl 盐敏感大鼠中的作用来阐明这些机制。
8 周龄雄性 Dahl 盐敏感大鼠给予正常盐（0.6%NaCl）或高盐（8%NaCl）饮食 8 周。一部分给予高盐饮食的大鼠同时给予非布司他（3mg/kg/天）治疗。此外，还在给予高盐饮食 4 或 8 周后，检查非布司他（3mg/kg/天）的急性作用。
非布司他治疗 8 周可减轻高盐饮食引起的高血压、肾功能障碍、肾小球损伤和肾间质纤维化。非布司他治疗可减少尿 H2O2 和丙二醛排泄以及肾硫代巴比妥酸反应物质含量。高盐饮食增加了近端小管和髓质间质中的黄嘌呤氧化还原酶活性和表达。非布司他完全抑制黄嘌呤氧化还原酶活性，并减轻高盐饮食引起的黄嘌呤氧化还原酶表达增加。非布司他在给予高盐饮食 4 或 8 周后，短暂增加尿量和 Na+排泄，而血压或尿肌酐排泄无变化。
非布司他可改善 Dahl 盐敏感大鼠的高盐饮食引起的高血压和肾脏损伤，并减轻肾脏氧化应激。非布司他的降压作用部分可能通过利尿和排钠作用介导。
